To further understand the processes controlling tissue fibrosis, we characterized the effect of recombinant gamma, alpha A, alpha D, and beta interferons on the proliferation of slowly and rapidly proliferating normal human lung fibroblasts. In addition, we investigated the role of fibroblast prostaglandin production in mediating the effects that were noted. Gamma interferon was capable of bidirectional modulation of fibroblast growth since it stimulated the proliferation of quiescent cells and inhibited the proliferation of rapidly proliferating cells. In contrast, alpha A, alpha D, and beta interferons did not stimulate the proliferation of quiescent cells, but did inhibit the proliferation of rapidly proliferating cells. Gamma, alpha A, alpha D, and beta did not stimulate E series prostaglandin production by rapidly proliferating fibroblasts, and blocking fibroblast prostaglandin production did not reverse the inhibition of fibroblast growth caused by these interferons. Thus, gamma interferon can stimulate or inhibit, whereas alpha A, alpha D, and beta interferons only inhibit the growth of normal human lung fibroblasts. In addition, the inhibition of fibroblast growth caused by all 4 interferons appears to be independent of fibroblast prostaglandin production.